AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

The term rickets evolved from the old English word wrick, which means "to twist." This twisting or bending of the bones has been known to physicians since antiquity and, as with many diseases, was gradually found to encompass more than a single etiology. Since the early 20th century, ultraviolet radiation or vitamin D ingestion has been recognized as a cure for nutritional rickets, although certain forms of rachitic disease have remained refractory to this therapy. Study of these refractory cases has revealed low serum phosphate concentration as a common factor. Familial occurrence of this condition led to the diagnosis of familial hypophosphatemic rickets. Treatment with vitamin D produced no change in the rachitic state of these patients, even at rather high doses, leading to the term vitamin D-resistant rickets.

In 1958, the definitive study of familial hypophosphatemic rickets gave legitimacy to the formal name of X-linked hypophosphatemic rickets.¹ This amply detailed and large pedigree study defined hypophosphatemia as a highly reliable disease marker.

Serum phosphate reduction in relation to normal levels was equal for male and female subjects. Females generally had markedly less bone disease than males, suggesting the random inactivation of the affected X chromosome in females, as might be expected from the Lyon hypothesis. However, lowered serum phosphate levels correlated with an equal degree of renal tubular reduction of tubular time of maximal concentration (T_max) of phosphate in both sexes, pointing to an additional factor in the creation of the bone disease in affected males. Although Clinical response to different analogues of cholecalciferol suggests that the deficient factor may be 1-alpha-hydroxylation of the 25-hydroxycholecalciferol metabolite released from the liver; however, no direct evidence has been reported.

Pathophysiology

Several of the most vexing questions about the underlying mechanism that causes the clinical phenotype of X-linked hypophosphatemia remain unanswered. A key question awaiting explication concerns the equal degree of reduction in tubular T_max in both sexes juxtaposed against the significant difference in clinical disease between the sexes. Another question involves the relationship between the reduced tubular T_max and the reduced 1-alpha-hydroxylation of 25-hydroxycholecalciferol.

Great strides have been made in recent years, particularly with the cloning of the mutant gene known as PHEX. The change created in the gene is a loss-of-function mutation and results in reduced breakdown; hence, circulatory clearance of a substance known as fibroblast growth factor (FGF23). FGF23 acts on the kidney to cause increased phosphate excretion and decreased alpha-1 hydroxylase activity. The gene product is now known to be a zinc-metallopeptidase.

The PHEX gene, found on the X chromosome, is thought to protect an extracellular matrix glycoprotein (MEPES) from proteolysis through formation of a Zn-dependent protein-protein interaction. A mutated PHEX gene could result in failure to form this interaction, leading to proteolysis and release of the C-terminal ASARM peptide, which possesses phosphaturic and mineralization-inhibiting properties. These 2 mechanisms acting in synergy could account for the massive hyperphosphaturia in this disorder.

The pathogenesis of this disorder is clear; phosphate wasting at the proximal tubule level is the basis of the affected individual's inability to establish normal ossification. This phenomenon is secondary to defective regulation of the sodium-phosphate cotransporter in the epithelial cell brush border. Normal phosphate reabsorption in response to 1 a,25-dihydroxycholecalciferol (calcitriol) provides clear evidence that the sodium-phosphate cotransporter is capable of proper function and is not intrinsically defective. This evidence also bolsters the hypothesis advanced above, which implicates an additional factor in the pathogenesis of the phosphaturia.

Inadequate levels of inorganic phosphate impair the function of mature osteoblasts (ie, bone matrix ossification), because formation of mature bone involves the precipitation of hydroxyapatite [3-Ca₃(PO₄)₂ : Ca(OH)₂] crystals. Although treatment with oral phosphate supplements should remedy the defect, all such attempts have failed. This failure could be due to the enhanced mineralization-inhibiting presence of ASARM peptide secondary to the mutated PHEX gene in bone.

The advantages of improved technology and hindsight now confirm that phosphate supplementation elicits a parathyroid hormone (PTH) response to the fall in serum calcium from the temporary surge in bone mineralization induced by phosphate ingestion. Following this surge is an immediate return to the initial status quo because PTH depresses phosphate reabsorption at the renal tubule. Recent data suggest that hyperparathyroidism may be a part of the clinical disorder preceding any therapy.

Although much has been learned about the pathophysiology of this fascinating disorder in the 4 decades since its original definition, a great deal more remains undiscovered.

Frequency

United States

The frequency is unknown.

Mortality/Morbidity

• The nomenclature alone indicates that the chief aspects of morbidity in X-linked hypophosphatemia are the metabolic processes linked to phosphate. Clinically, the most obvious of these aspects is the effect on bone formation and growth that causes very severe rickets, especially in affected males. The early development of rickets indicates alterations in the orderly processes of bone growth and remodeling that cause bone deformation.
• Abnormal dentine formation causes late dentition and spontaneous abscess formation.

Sex

• Although serum phosphate levels are similarly depressed in affected males and females, the degree of bone involvement is substantially less severe in heterozygous females.
• All hemizygous males are clinically affected.

Age

• As in all genetic disorders, the disease is present from conception.
• Infant birth weight is generally normal, but early growth may be slower than normal. The author's experience indicates abnormalities are common at birth, including cranial synostosis and increased bone density.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• The earliest clinical sign of hypophosphatemic rickets is usually a somewhat slowed growth rate in the first year of life. The next clinical sign is the patient's reluctance to bear weight when beginning to stand or walk.
• Oddly, affected patients do not have seizures and other systemic signs related to muscle function or oxidative metabolism.
• To the degree that heterozygous females are affected, patients' maternal family history is likely to include short stature and rickets. Short stature in men also is expected.
• Older children may have a history of late dentition or multiple dental abscesses.

Physical

• Affected newborns have normal weight, but infants may show growth retardation. Intellectual development is unaffected.
• Widened joint spaces and flaring at the knees may become apparent in children by their first birthday, particularly in boys. When a child begins to stand and walk, bowing of the weight-bearing long bones quickly becomes clinically evident.
• Dentition may be absent or delayed in very young children; older children may experience multiple dental abscesses.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Renal tubular acidosis
Hereditary hypophosphatemic rickets with hypocalciuria
Fanconi syndrome (types I and II)
Vitamin D-dependent rickets (types I and II)
Vitamin D-deficient rickets
Pseudohypoparathyroidism

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Begin clinical laboratory evaluation of rickets with assessment of serum calcium, phosphate, and alkaline phosphatase levels.
• In hypophosphatemic rickets, calcium levels may be within or slightly below the reference range; alkaline phosphatase levels are significantly above the reference range.
• Carefully evaluate serum phosphate levels in the first year of life because the concentration reference range for infants (5.0-7.5 mg/dL) is high compared with adults (2.7-4.5 mg/dL). Hypophosphatemia can easily be missed in a baby.
• Serum parathyroid hormone levels are within the reference range or slightly elevated, while calcitriol levels are low or within the lower reference range.
• Most importantly, urinary loss of phosphate is above the reference range.

Imaging Studies

• In all cases of rickets, the study of choice is radiography of the wrists, knees, ankles, and long bones. No pathognomonic sign on radiographs distinguishes hypophosphatemic rickets from any other etiology.
• In children receiving treatment, periodic renal ultrasonography studies are important to monitor for development of nephrocalcinosis. Originally thought to be a sequela of the disease, this complication is now recognized as an iatrogenic result of therapy. Monitoring the ratio of calcium to creatinine in the urine is also important. A ratio of more than 0.25:1 requires reduction of the vitamin D dosage to avoid nephrocalcinosis.

Other Tests

• Renal tubular phosphate reabsorption
• • The renal tubular reabsorption of phosphate (TRP) is calculated with the following formula:
    
    1 - [Phosphate Clearance (CPi) / Creatinine Clearance (C_cr)] X 100
  • The following formula calculates CPi:
    
    [Urine Phosphate (mg/dL) X Volume (mL/min)] / Plasma Phosphate (mg/dL)  
  • By substituting creatinine values for phosphate in the same formula, C_cr can also be calculated.
  • A single, early-morning urine sample can be used because CPi divided by C_cr causes units of urine volume to cancel each other.
  • The TRP in X-linked hypophosphatemia is 60%; normal TRP exceeds 90% at the same reduced plasma phosphate concentration.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

• Treatment can be safely administered on an outpatient basis, although serum calcium concentrations must be periodically and carefully monitored. Conscientious follow-up is essential.
• The usual vitamin D preparations are not useful for treatment in this disorder because they lack significant 1-alpha-hydroxylase activity. Original treatment protocols advocated vitamin D at levels of 25,000-50,000 U/d (at the lower limit of toxic dosage), which placed the patient in jeopardy of frequent hypercalcemic episodes. Calcitriol is now more widely available and substantially diminishes, but does not eliminate, this risk. Amiloride and hydrochlorothiazide are administered to enhance calcium reabsorption and to reduce the risk of nephrocalcinosis.

Surgical Care

• Osteotomy to realign extremely distorted leg curvatures may be necessary for children whose diagnosis was delayed or whose initial treatment was inadequate. Skull deformity may require treatment for synostosis.
• Spontaneous abscesses often require periodic dental procedures.

Consultations

Consult a nephrologist for help treating any patient with possible kidney involvement.

Activity

If a patient is able, no activity restrictions are needed. Affected individuals obviously should not engage in contact sports until rickets is completely healed.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Treatment options include calcitriol, growth hormone, phosphates, and anticalciurics to promote healthy bone growth and diminish mineral loss associated with hypophosphatemic rickets.

Drug Category: Vitamin D

Standard protocol for treatment of familial hypophosphatemic rickets includes the use of 1,25-dihydroxy-vitamin D (calcitriol). Use of calcitriol in place of standard vitamin D obviates near-toxic dosage of the latter, avoids fat storage of parent vitamin D, and diminishes the danger of hypercalcemia.

Drug Category: Growth Hormone

These agents enhance growth in affected children.

Drug Category: Phosphate replacement

Massive urinary phosphate loss is a problem intrinsic to the disorder, and the phosphate must be replaced.

Drug Category: Diuretics

Thiazides are anticalciuric, an effect that can assist in counteracting the tendency for bone Ca loss.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Healing of the rachitic changes typically occurs within 6-8 weeks of instituting treatment. During this time, maintain the calcitriol within the recommended dosage to maintain serum calcium and phosphate levels within reference ranges. Monitor these levels weekly over the first 2-3 months of treatment. Urinary calcium and phosphate excretion monitoring also are important.
• The patient's requirements for calcium deposition and vitamin D to expedite the healing process diminish as healing progresses; thus, the patient becomes highly susceptible to hypercalcemia during this phase. Consider reducing the calcitriol dosage at this time, guided by the weekly calcium and phosphorus measurements, until a reduced and stable dosage is reached.

In/Out Patient Meds

• Calcitriol
• Neutralized, buffered phosphate solution
• Hydrochlorothiazide
• Amiloride
• Human recombinant growth hormone

Complications

• An outstanding feature of familial hypophosphatemic rickets is short stature. The short stature associated with this condition is disproportionate, resulting from deformity and growth retardation of lower extremities. This short stature has been addressed in clinical trials by adding growth hormone (GH) to the usual treatment protocol to stimulate growth plates in the long bones. At least one study has reported a mild degree of disproportionate truncal growth, which requires further evaluation. Although GH therapy has been effective in promoting short-term growth, its high cost discourages widespread use. As a result, many properly treated children ultimately achieve less-than-average height.
• Acute hypercalcemia (with resulting irritability, confusion, and potential seizures) can occur during treatment. Nephrocalcinosis, the long-term result of overaggressive therapy, may be more damaging. Although ultrasonography reveals that 47% of properly treated patients show evidence of nephrocalcinosis, the condition apparently does not progress to renal failure.
• Hypertension has been reported in older children under treatment as a consequence of persistent hyperparathyroidism. Nephrocalcinosis did not need to be present for hypertension to occur. Consequently, patients under treatment should be carefully monitored for laboratory signs of hyperparathyroidism.

Prognosis

• Apart from the short stature of most affected adults, the prognosis for a normal lifespan and normal health is good.

Patient Education

• Provide genetic counseling following initial diagnosis to help an affected child's parents understand the hereditary basis of the condition. Counseling must be provided with sensitivity to avoid family conflict.
• The patient and family need to know the importance of close follow-up to avoid complications.
• Unless a concomitant GH deficiency is observed, administration of biosynthetic GH for growth promotion has not been approved. Only preliminary evidence of improved final height with GH therapy has been reported.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• The physician must be keenly aware of the differences in serum phosphate reference ranges for infants and adults to avoid missing the primary diagnostic indicator. Misdiagnosis of the etiology significantly delays healing.
• A linear correlation has been noted between the mean phosphate supplementation and the degree of nephrocalcinosis; more than 150 mg/kg/d markedly increases the severity of calcium deposition. Thus, the dose should not exceed 100 mg/kg/d; the recommended amount is 50 mg/kg/d.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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2. Alon US, Monzavi R, Lilien M, et al. Hypertension in hypophosphatemic rickets--role of secondary hyperparathyroidism. Pediatr Nephrol. Feb 2003;18(2):155-8. [Medline].
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17. Quarles LD. FGF23, PHEX, and MEPE regulation of phosphate homeostasis and skeletal mineralization. Am J Physiol Endocrinol Metab. Jul 2003;285(1):E1-9. [Medline].
18. Sabbagh Y, Boileau G, Campos M, et al. Structure and function of disease-causing missense mutations in the PHEX gene. J Clin Endocrinol Metab. May 2003;88(5):2213-22. [Medline].
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20. Sochett E, Doria AS, Henriques F, et al. Growth and metabolic control during puberty in girls with X-linked hypophosphataemic rickets. Horm Res. 2004;61(5):252-6. [Medline].
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Article Last Updated: Aug 24, 2007